title: Dynamics of the major histocompatibility complex class I processing and presentation pathway in the course of malaria parasite development in human hepatocytes: implications for vaccine development.
abstract: Control of parasite replication exerted by MHC class I restricted CD8+ T-cells in the liver is critical for vaccination-induced protection against malaria. While many intracellular pathogens subvert the MHC class I presentation machinery, its functionality in the course of malaria replication in hepatocytes has not been characterized. Using experimental systems based on specific identification, isolation and analysis of human hepatocytes infected with P. berghei ANKA GFP or P. falciparum 3D7 GFP sporozoites we demonstrated that molecular components of the MHC class I pathway exhibit largely unaltered expression in malaria-infected hepatocytes until very late stages of parasite development. Furthermore, infected cells showed no obvious defects in their capacity to upregulate expression of different molecular components of the MHC class I machinery in response to pro-inflammatory lymphokines or trigger direct activation of allo-specific or peptide-specific human CD8+ T-cells. We further demonstrate that ectopic expression of circumsporozoite protein does not alter expression of critical genes of the MHC class I pathway and its response to pro-inflammatory cytokines. In addition, we identified supra-cellular structures, which arose at late stages of parasite replication, possessed the characteristic morphology of merosomes and exhibited nearly complete loss of surface MHC class I expression. These data have multiple implications for our understanding of natural T-cell immunity against malaria and may promote development of novel, efficient anti-malaria vaccines overcoming immune escape of the parasite in the liver.
authors.affiliation: W. Harry Feinstone Department of Molecular Microbiology and Immunology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, Maryland, United States of America.
authors.forename: Jinxia
authors.initials: J
authors.lastname: Ma
authors.forename: Stefanie
authors.initials: S
authors.lastname: Trop
authors.forename: Samantha
authors.initials: S
authors.lastname: Baer
authors.forename: Elian
authors.initials: E
authors.lastname: Rakhmanaliev
authors.forename: Zita
authors.initials: Z
authors.lastname: Arany
authors.forename: Peter
authors.initials: P
authors.lastname: Dumoulin
authors.forename: Hao
authors.initials: H
authors.lastname: Zhang
authors.forename: Julia
authors.initials: J
authors.lastname: Romano
authors.forename: Isabelle
authors.initials: I
authors.lastname: Coppens
authors.forename: Victor
authors.initials: V
authors.lastname: Levitsky
authors.forename: Jelena
authors.initials: J
authors.lastname: Levitskaya
mesh_terms: D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D017931:DNA Primers / Q000235:genetics; D015971:Gene Expression Regulation, Enzymologic / Q000502:physiology*; D005805:Genes, MHC Class I / Q000235:genetics / Q000276:immunology*; D022781:Hepatocytes / Q000276:immunology* / Q000469:parasitology; D006801:Humans; D008288:Malaria / Q000276:immunology* / Q000378:metabolism; D017780:Malaria Vaccines / Q000276:immunology; D010961:Plasmodium / Q000254:growth & development*; D015800:Protozoan Proteins / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D012098:Reproduction / Q000502:physiology; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D017931:DNA Primers; D017780:Malaria Vaccines; D015800:Protozoan Proteins; C041595:circumsporozoite protein, Protozoan